Diversity and patterns of regulation of nicotinic receptor subtypes.
Diversity and patterns of regulation of nicotinic receptor subtypes.
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烟碱受体亚型的多样性和调节模式。
DOI：
10.1111/j.1749-6632.1995.tb17471.x
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发表时间：
1995
影响因子：
5.2
通讯作者：
Lukas,RJ
中科院分区：
文献类型：
--
作者：
Lukas,RJ
烟碱乙酰胆碱受体（nAChR）是一种多相的大分子。’-”回想起来，令人惊讶的是，nAChR多样性的概念没有得到更迅速和广泛的接受。从Dale、Paton和他们同时代的人开始的比较药理学研究清楚地表明，尼古丁药物在脊椎动物神经肌肉连接处和自主神经节的作用存在差异。5-7其他药理学研究也表明，中枢神经系统（CNS）中也存在不同于肌肉和神经节中发现的nAChR亚型，这是基于对小型尼古丁激动剂或拮抗剂的不同敏感性。^^最近的研究将这些观察结果扩展到不同类别的神经毒素，如班加罗毒素和新硫脲毒素，以及更简化的制备~。在排除可能的药代动力学并发症的情况下，只有在nAChR存在结构多样性的情况下，才能解释肌肉、神经节和大脑中nAChR功能多样性的证据。在成功地阐明了来自电器官的肌肉型nAChR的结构，并证明了肌肉型nAChR是由同源但不同的~亚基组成的之后，利用蛋白质化学、放射配体结合和免疫化学技术的研究也证明了结构上不同的nAChR亚型的存在。z4大约在基于功能和放射配体结合研究将药理学特征分配给这些不同实体的时候，重组DNA技术的应用揭示了存在一个同源但遗传上不同的nAChR亚基家族，这些亚基不是在肌肉中表达，而是在神经系统中表达。*~ J~目前，已经鉴定出至少15种不同的nAChR亚基基因，其中包括5种在肌肉中表达的nAChR亚基和10种“神经元”nAChR亚基。那些在假定的烟碱配体结合活性位点附近具有串联半胱氨酸残基的神经元nAChR亚基（即保留a1亚基的配体结合结构域的特征）被定义为亚基，而那些缺乏串联半胱氨酸残基但保留肌肉nAChR亚基的其他特征的神经元nAChR亚基被定义为非a亚基，或者更普遍的是p亚基。其中一些基因的组织和/或大脑区域特异性表达限制了可能的分配
Nicotinic acetylcholine receptors (nAChR) arc now known to exist as a heterogenous group of macromolecules.’-“In retrospect, it is surprising that the concept of nAChR diversity was not more rapidly and widely accepted. Comparative pharmacological studies dating from the times of Dale, Paton, and their contemporaries clearly indicated differences in nicotinic drug actions at the vertebrate neuromuscular junction and at autonomic ganglia. 5-7 Other pharmacological studies also suggested that nAChR subtypes distinct from those found in muscle and ganglia exist in the central nervous system (CNS) as well, based on differing sensitivity to small nicotinic agonists or antagonist^.^^ More recent studies extended those observations to different classes of neurotoxins, such as the bungarotoxins and neosurugatoxin, and to more reduced preparation~.~.~ J@~* This evidcncc for nAChR functional diversity in muscle, ganglia, and brain can only be explained-given that possible complications of pharmacokinetics are excluded-if there is structural diversity of nAChR. Following the success in elucidation of the structure of muscle-type nAChR from the electric organ and the demonstration that muscle-type nAChR are composed of homologous, but distinct,~ ubunits, l~-*~ studies employing protein chemical, radioligand binding, and immunochemical techniques also demonstrated the existence of structurally distinct nAChR subtypes. z4 About the time that pharmacological features were being assigned to these distinct entitics on the basis of functional and radioligand binding studies, the application of recombinant DNA tcchniques revealed the existence of a family of homologous, but genetically distinct, nAChR subunits that were expressed not in muscle, but in thc nervous sy~ tem.*~ J~ Currently, at least 15 different nAChR subunit genes, including 5 expressed in muscle and 10 “neuronal” nAChR subunits, have been identified. Those neuronal nAChR subunits that have tandem cysteine residues near the putative nicotinic ligand-binding active site (ie, in which features of the ligand-binding domain of the a1 subunit are preserved) are defined as a subunits, whereas those neuronal nAChR subunits that lack the tandem cysteine residues but that retain other features of muscle nAChR subunits are defined as non-a or, more popularly, p subunits. Tissue-and/or brain region-specific expression of some of these genes restricts possible assignments to